Search

Your search keyword '"Laffan, Michael"' showing total 22 results
Start Over Author "Laffan, Michael" Topic hemorrhage
22 results on '"Laffan, Michael"'

1. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A.

Author

Ozelo MC, Mahlangu J, Pasi KJ, Giermasz A, Leavitt AD, Laffan M, Symington E, Quon DV, Wang JD, Peerlinck K, Pipe SW, Madan B, Key NS, Pierce GF, O'Mahony B, Kaczmarek R, Henshaw J, Lawal A, Jayaram K, Huang M, Yang X, Wong WY, and Kim B

Subjects
Adult, Humans, Male, Alanine Transaminase blood, Dependovirus, Factor VIII therapeutic use, HIV Seronegativity, Infusions, Intravenous, Intention to Treat Analysis, Genetic Therapy methods, Genetic Vectors, Hemophilia A complications, Hemophilia A therapy, Hemorrhage epidemiology, Hemorrhage etiology, Hemorrhage prevention & control
Abstract

Background: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study., Methods: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×10 13 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results., Results: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants., Conclusions: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.)., (Copyright © 2022 Massachusetts Medical Society.)

Published
2022
Full Text
View/download PDF

2. Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.

Author

Downes K, Megy K, Duarte D, Vries M, Gebhart J, Hofer S, Shamardina O, Deevi SVV, Stephens J, Mapeta R, Tuna S, Al Hasso N, Besser MW, Cooper N, Daugherty L, Gleadall N, Greene D, Haimel M, Martin H, Papadia S, Revel-Vilk S, Sivapalaratnam S, Symington E, Thomas W, Thys C, Tolios A, Penkett CJ, Ouwehand WH, Abbs S, Laffan MA, Turro E, Simeoni I, Mumford AD, Henskens YMC, Pabinger I, Gomez K, and Freson K

Subjects
Female, Gene Dosage, Hemostasis genetics, Humans, Male, Blood Platelet Disorders diagnosis, Blood Platelet Disorders genetics, Hemorrhage diagnosis, Hemorrhage genetics, High-Throughput Nucleotide Sequencing, Thrombosis diagnosis, Thrombosis genetics
Abstract

A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD., (© 2019 by The American Society of Hematology.)

Published
2019
Full Text
View/download PDF

3. Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding.

Author

Westbury SK, Canault M, Greene D, Bermejo E, Hanlon K, Lambert MP, Millar CM, Nurden P, Obaji SG, Revel-Vilk S, Van Geet C, Downes K, Papadia S, Tuna S, Watt C, Freson K, Laffan MA, Ouwehand WH, Alessi MC, Turro E, and Mumford AD

Subjects
Alleles, Base Sequence, Female, Humans, Male, Pedigree, Blood Platelets pathology, Guanine Nucleotide Exchange Factors genetics, Hemorrhage genetics, Mutation genetics
Abstract

Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2 , which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included 5 high-impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signaling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring ≥1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 5'-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation., (© 2017 by The American Society of Hematology.)

Published
2017
Full Text
View/download PDF

4. Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia.

Author

Sivapalaratnam S, Westbury SK, Stephens JC, Greene D, Downes K, Kelly AM, Lentaigne C, Astle WJ, Huizinga EG, Nurden P, Papadia S, Peerlinck K, Penkett CJ, Perry DJ, Roughley C, Simeoni I, Stirrups K, Hart DP, Tait RC, Mumford AD, Laffan MA, Freson K, Ouwehand WH, Kunishima S, and Turro E

Subjects
Alleles, Blood Platelets pathology, Case-Control Studies, Female, Gene Expression, Genes, Dominant, Genome, Human, Hemorrhage diagnosis, Hemorrhage metabolism, Hemorrhage pathology, High-Throughput Nucleotide Sequencing, Humans, Male, Pedigree, Platelet Count, Thrombocytopenia diagnosis, Thrombocytopenia metabolism, Thrombocytopenia pathology, Blood Platelets metabolism, Hemorrhage genetics, Mutation, Platelet Glycoprotein GPIb-IX Complex genetics, Thrombocytopenia genetics
Abstract

The von Willebrand receptor complex, which is composed of the glycoproteins Ibα, Ibβ, GPV, and GPIX, plays an essential role in the earliest steps in hemostasis. During the last 4 decades, it has become apparent that loss of function of any 1 of 3 of the genes encoding these glycoproteins (namely, GP1BA, GP1BB, and GP9) leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia, but only 2 tentative reports exist of such a variant in GP1BB By analyzing data from a collection of more than 1000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. To strengthen our findings, we sought further cases in 2 additional collections in the United Kingdom and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying 1 of 9 rare variants in GP1BB., (© 2017 by The American Society of Hematology.)

Published
2017
Full Text
View/download PDF

5. A whole genome approach to platelet and bleeding disorders.

Author

Laffan M

Subjects
Chromosome Mapping methods, Exome genetics, Genetic Markers genetics, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Humans, Prevalence, Blood Platelet Disorders epidemiology, Blood Platelet Disorders genetics, Genome, Human genetics, Hemorrhage epidemiology, Hemorrhage genetics, Polymorphism, Single Nucleotide genetics
Abstract

The sequencing of hundreds of thousands of human exomes and hundreds of thousands of whole genomes is providing a progressively accurate and complete catalogue of human genetic variation. The initial studies to use genome wide data to help understand platelet disorders performed genome wide association studies to identify loci linked to variations in blood cell parameters. These studies used normal variation to find corresponding genetic variation. We next wished to investigate the genetic basis of bleeding disorders which may also provide a key to novel genes regulating platelet and haemostatic functions. The BRIDGE consortium (www.bridgestudy.org) is funded by the NIHR and brings together 13 rare disease gene discovery projects. The aim of these projects is to investigate as yet undiagnosed rare inherited diseases and identify the underlying mutational basis. We have used a cluster analysis based on the Human Phenotype Ontology in combination with next generation sequencing techniques to help identify patients with similar phenotypes which we hypothesise will arise from defects in the same gene. Preliminary results validate the clustering approach and have also resulted in a number of novel genes important for normal and pathogenic platelet physiology.

Published
2016
Full Text
View/download PDF

6. A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders.

Author

Simeoni I, Stephens JC, Hu F, Deevi SV, Megy K, Bariana TK, Lentaigne C, Schulman S, Sivapalaratnam S, Vries MJ, Westbury SK, Greene D, Papadia S, Alessi MC, Attwood AP, Ballmaier M, Baynam G, Bermejo E, Bertoli M, Bray PF, Bury L, Cattaneo M, Collins P, Daugherty LC, Favier R, French DL, Furie B, Gattens M, Germeshausen M, Ghevaert C, Goodeve AC, Guerrero JA, Hampshire DJ, Hart DP, Heemskerk JW, Henskens YM, Hill M, Hogg N, Jolley JD, Kahr WH, Kelly AM, Kerr R, Kostadima M, Kunishima S, Lambert MP, Liesner R, López JA, Mapeta RP, Mathias M, Millar CM, Nathwani A, Neerman-Arbez M, Nurden AT, Nurden P, Othman M, Peerlinck K, Perry DJ, Poudel P, Reitsma P, Rondina MT, Smethurst PA, Stevenson W, Szkotak A, Tuna S, van Geet C, Whitehorn D, Wilcox DA, Zhang B, Revel-Vilk S, Gresele P, Bellissimo DB, Penkett CJ, Laffan MA, Mumford AD, Rendon A, Gomez K, Freson K, Ouwehand WH, and Turro E

Subjects
Case-Control Studies, DNA Copy Number Variations, Female, Genetic Association Studies methods, Humans, Male, Mutation, Polymorphism, Single Nucleotide, Sequence Analysis, DNA methods, Blood Platelet Disorders genetics, Genetic Predisposition to Disease, Hemorrhage genetics, High-Throughput Nucleotide Sequencing methods, Thrombosis genetics
Abstract

Inherited bleeding, thrombotic, and platelet disorders (BPDs) are diseases that affect ∼300 individuals per million births. With the exception of hemophilia and von Willebrand disease patients, a molecular analysis for patients with a BPD is often unavailable. Many specialized tests are usually required to reach a putative diagnosis and they are typically performed in a step-wise manner to control costs. This approach causes delays and a conclusive molecular diagnosis is often never reached, which can compromise treatment and impede rapid identification of affected relatives. To address this unmet diagnostic need, we designed a high-throughput sequencing platform targeting 63 genes relevant for BPDs. The platform can call single nucleotide variants, short insertions/deletions, and large copy number variants (though not inversions) which are subjected to automated filtering for diagnostic prioritization, resulting in an average of 5.34 candidate variants per individual. We sequenced 159 and 137 samples, respectively, from cases with and without previously known causal variants. Among the latter group, 61 cases had clinical and laboratory phenotypes indicative of a particular molecular etiology, whereas the remainder had an a priori highly uncertain etiology. All previously detected variants were recapitulated and, when the etiology was suspected but unknown or uncertain, a molecular diagnosis was reached in 56 of 61 and only 8 of 76 cases, respectively. The latter category highlights the need for further research into novel causes of BPDs. The ThromboGenomics platform thus provides an affordable DNA-based test to diagnose patients suspected of having a known inherited BPD., (© 2016 by The American Society of Hematology.)

Published
2016
Full Text
View/download PDF

7. A dominant gain-of-function mutation in universal tyrosine kinase SRC causes thrombocytopenia, myelofibrosis, bleeding, and bone pathologies.

Author

Turro E, Greene D, Wijgaerts A, Thys C, Lentaigne C, Bariana TK, Westbury SK, Kelly AM, Selleslag D, Stephens JC, Papadia S, Simeoni I, Penkett CJ, Ashford S, Attwood A, Austin S, Bakchoul T, Collins P, Deevi SV, Favier R, Kostadima M, Lambert MP, Mathias M, Millar CM, Peerlinck K, Perry DJ, Schulman S, Whitehorn D, Wittevrongel C, De Maeyer M, Rendon A, Gomez K, Erber WN, Mumford AD, Nurden P, Stirrups K, Bradley JR, Raymond FL, Laffan MA, Van Geet C, Richardson S, Freson K, and Ouwehand WH

Subjects
Animals, Blood Platelets pathology, COS Cells, Chlorocebus aethiops, Female, Hematopoiesis, Hemorrhage complications, Humans, Male, Pedigree, Phenotype, Primary Myelofibrosis complications, Thrombocytopenia complications, Transfection, Zebrafish, Bone and Bones pathology, Hemorrhage genetics, Mutation genetics, Primary Myelofibrosis genetics, Thrombocytopenia genetics, src-Family Kinases genetics
Abstract

The Src family kinase (SFK) member SRC is a major target in drug development because it is activated in many human cancers, yet deleterious SRC germline mutations have not been reported. We used genome sequencing and Human Phenotype Ontology patient coding to identify a gain-of-function mutation in SRC causing thrombocytopenia, myelofibrosis, bleeding, and bone pathologies in nine cases. Modeling of the E527K substitution predicts loss of SRC's self-inhibitory capacity, which we confirmed with in vitro studies showing increased SRC kinase activity and enhanced Tyr(419) phosphorylation in COS-7 cells overexpressing E527K SRC. The active form of SRC predominates in patients' platelets, resulting in enhanced overall tyrosine phosphorylation. Patients with myelofibrosis have hypercellular bone marrow with trilineage dysplasia, and their stem cells grown in vitro form more myeloid and megakaryocyte (MK) colonies than control cells. These MKs generate platelets that are dysmorphic, low in number, highly variable in size, and have a paucity of α-granules. Overactive SRC in patient-derived MKs causes a reduction in proplatelet formation, which can be rescued by SRC kinase inhibition. Stem cells transduced with lentiviral E527K SRC form MKs with a similar defect and enhanced tyrosine phosphorylation levels. Patient-derived and E527K-transduced MKs show Y419 SRC-positive stained podosomes that induce altered actin organization. Expression of mutated src in zebrafish recapitulates patients' blood and bone phenotypes. Similar studies of platelets and MKs may reveal the mechanism underlying the severe bleeding frequently observed in cancer patients treated with next-generation SFK inhibitors., (Copyright © 2016, American Association for the Advancement of Science.)

Published
2016
Full Text
View/download PDF

9. Efficacy of recombinant activated factor VII in unselected patients with uncontrolled haemorrhage: a single centre experience.

Author

Payne EM, Brett SJ, and Laffan MA

Subjects
Adolescent, Adult, Aged, Antifibrinolytic Agents therapeutic use, Blood Component Transfusion, Combined Modality Therapy, Dose-Response Relationship, Drug, Factor VII administration & dosage, Factor VIIa, Female, Hemorrhage etiology, Humans, Male, Middle Aged, Platelet Count, Postoperative Hemorrhage therapy, Recombinant Proteins administration & dosage, Recombinant Proteins therapeutic use, Retrospective Studies, Treatment Outcome, Factor VII therapeutic use, Hemorrhage drug therapy
Abstract

Recombinant activated factor VII (rFVIIa /Novoseven) has been used in a wide variety of circumstances as a treatment for uncontrolled bleeding. We present a retrospective report of the use of rFVIIa in 40 consecutive patients without inherited bleeding disorders in a single centre. Twenty-one (68%) of the 31 patients whose response to rFVIIa was documented showed a reduction or cessation in bleeding; in nine patients (29%) bleeding was unchanged and in one patient (3%) bleeding increased despite rFVIIa. One person suffered a thrombotic stroke after rFVIIa treatment. There were no other adverse events directly attributable to rFVIIa. Twenty-four patients (60%) died during the hospital admission in which the rFVIIa was administered. Twelve patients (30%) who received rFVIIa had bleeding secondary to haematological malignancy and 21 patients (53%) had bleeding complicating a surgical procedure. There were 11 deaths (92%) in the haematological malignancy group and 10 deaths (48%) in the surgical group. Patients with haematological malignancy received a significantly greater median number of doses of rFVIIa than patients with surgical bleeding complications (three versus one dose, P = 0.04). We conclude that rFVIIa can be used safely in uncontrolled haemorrhage and the majority of patients show a response.

Published
2006
Full Text
View/download PDF

10. Recombinant FVIIa in the management of uncontrolled hemorrhage.

Author

O'Connell NM, Perry DJ, Hodgson AJ, O'Shaughnessy DF, Laffan MA, and Smith OP

Subjects
Adult, Aged, Aged, 80 and over, Antifibrinolytic Agents therapeutic use, Blood Component Transfusion, Factor VIIa adverse effects, Female, Hemoglobins, Hemorrhage surgery, Humans, Male, Middle Aged, Product Surveillance, Postmarketing, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Retrospective Studies, Treatment Outcome, Factor VIIa administration & dosage, Hemorrhage drug therapy, Hemostasis drug effects
Abstract

Background: Recombinant FVIIa (rFVIIa/NovoSeven) is a novel hemostatic agent originally developed to treat patients with hemophilia who had developed inhibitors. Several case reports have suggested that rFVIIa may be effective in treating patients without a pre-existing bleeding disorder who have uncontrolled bleeding., Study Design and Methods: Data on the efficacy and safety of rFVIIa in the treatment of massive hemorrhage were obtained retrospectively from the NovoSeven extended-use data collection system., Results: A total of 40 patients received rFVIIa for uncontrolled bleeding, and in these patients, bleeding stopped or decreased in 32 (80%). Blood product usage was significantly decreased after rFVIIa administration. Thromboembolic events occurred in three patients with additional risk factors for thrombosis. Of 40 patients, 23 (57.5%) died. Bleeding was the direct cause of death in seven cases (all within 24 hr of administration of rFVIIa). The remaining 16 deaths were the result of sepsis, multi-organ failure, or the underlying disease., Conclusions: In this retrospective study of data voluntarily submitted to a web-based drug surveillance program, we present preliminary results on the use of rFVIIa in nonhemophilia patients with bleeding. Although some efficacy is suggested, there was a high mortality rate from nonhemorrhagic causes. Randomized controlled trials are needed to properly assess the role of rFVIIa in the management of hemorrhage.

Published
2003
Full Text
View/download PDF

11. Analysis and results of the recombinant factor VIIa extended-use registry.

Author

Laffan M, O'Connell NM, Perry DJ, Hodgson AJ, O'Shaughnessy D, and Smith OP

Subjects
Adult, Aged, Aged, 80 and over, Antifibrinolytic Agents administration & dosage, Antifibrinolytic Agents therapeutic use, Comorbidity, Factor VII administration & dosage, Factor VII adverse effects, Factor VIIa, Female, Hemorrhage epidemiology, Hemostatics administration & dosage, Hemostatics adverse effects, Humans, Ireland epidemiology, Male, Middle Aged, Recombinant Proteins administration & dosage, Recombinant Proteins adverse effects, Safety, Thrombophilia complications, Thrombosis chemically induced, Thrombosis etiology, Treatment Outcome, United Kingdom epidemiology, Factor VII therapeutic use, Hemorrhage drug therapy, Hemostatics therapeutic use, Recombinant Proteins therapeutic use, Registries statistics & numerical data
Abstract

This paper describes the analysis of recombinant factor VIIa (rFVIIa; NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) use in 40 patients with intractable bleeding in the UK. All cases were reported on the 'rFVIIa extended use database' (Traumanet) between its launch in February 1999 and 12 March 2002. Twenty-one other cases reporting rFVIIa use in different circumstances were excluded from the analysis. Recombinant FVIIa was effective in stopping or markedly reducing blood loss in 80% of patients; 20% of patients did not respond to treatment. Non-responders tended to have more deranged coagulation and lower platelet counts compared with responders. Despite a wide range of underlying illnesses, including malignancy and sepsis, few patients suffered adverse events. Thrombotic events occurred in three of 40 (7.5%) patients and these patients were considered as already at risk of thrombosis from other causes. The data suggest that rFVIIa is safe and effective therapy in patients with uncontrollable haemorrhage.

Published
2003
Full Text
View/download PDF

12. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, de Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, and Le Gal, Grégoire

Subjects
Clinical Trials and Supportive Activities, Clinical Research, Comparative Effectiveness Research, Cardiovascular, Good Health and Well Being, Aged, Anticoagulants, COVID-19, Critical Illness, Female, Hemorrhage, Heparin, Hospital Mortality, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Respiration, Artificial, Thrombosis, Treatment Failure, COVID-19 Drug Treatment, REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundThrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.MethodsIn an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge.ResultsThe trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

Published
2021

13. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A

Author

Mahlangu, Johnny, Kaczmarek, Radoslaw, von Drygalski, Annette, Shapiro, Susan, Chou, Sheng-Chieh, Ozelo, Margareth C, Kenet, Gili, Peyvandi, Flora, Wang, Michael, Madan, Bella, Key, Nigel S, Laffan, Michael, Dunn, Amy L, Mason, Jane, Quon, Doris V, Symington, Emily, Leavitt, Andrew D, Oldenburg, Johannes, Chambost, Hervé, Reding, Mark T, Jayaram, Kala, Yu, Hua, Mahajan, Reena, Chavele, Konstantia-Maria, Reddy, Divya B, Henshaw, Joshua, Robinson, Tara M, Wong, Wing Yen, Pipe, Steven W, GENEr8-1 Trial Group, Hermans, Cédric, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, and UCL - (SLuc) Centre de malformations vasculaires congénitales

Subjects
Male, Factor VIII, Recombinant Fusion Proteins, Gene Transfer Techniques, Humans, Hemorrhage, General Medicine, Hemophilia A, Half-Life
Abstract

BACKGROUND: Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously. METHODS: We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII. RESULTS: At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P

Published
2023

14. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, de Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Grégoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Gallego Lima, Felipe, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Lother, Sylvain A, Marten, Nicole, Saud Marinez, Andréa, Martinez, Mary, Mateos Garcia, Eduardo, Mavromichalis, Stavroula, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nicolau, Jose C, Nunez-Garcia, Brenda, Park, John J, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Pompilio, Mauricio, Quigley, John G, Rosenson, Robert S, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Santos, Mayler O, Satterwhite, Lewis, Saunders, Christina T, Schreiber, Jake, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Silva, Delcio G, Singhal, Aneesh B, Slutsky, Arthur S, Solvason, Dayna, Stanworth, Simon J, Turner, Anne M, van Bentum-Puijk, Wilma, van de Veerdonk, Frank L, van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zhong, Yongqi, Berry, Scott M, McArthur, Colin J, Neal, Matthew D, Hochman, Judith S, Webb, Steven A, Zarychanski, Ryan, Bradbury, Charlotte A [0000-0001-5248-8165], McVerry, Bryan J [0000-0002-1175-4874], Lawler, Patrick R [0000-0001-5155-5071], Carrier, Marc [0000-0001-8296-2972], Kim, Keri S [0000-0002-8480-4801], Houston, Brett L [0000-0002-8776-4083], Cushman, Mary [0000-0002-7871-6143], Tritschler, Tobias [0000-0002-8775-0511], Godoy, Lucas C [0000-0001-6171-1269], Gordon, Anthony C [0000-0002-0419-547X], Ahuja, Tania [0000-0003-1833-4124], Aryal, Diptesh [0000-0002-1431-8293], Baumann Kreuziger, Lisa [0000-0002-1171-0548], Beane, Abi [0000-0001-7046-1580], Coiffard, Benjamin [0000-0002-8896-5346], Detry, Michelle A [0000-0002-2794-1439], Escobedo, Jorge [0000-0003-1942-7402], Estcourt, Lise J [0000-0003-4309-9162], Everett, Brendan M [0000-0002-6331-5224], Fu, Zhuxuan [0000-0002-9190-195X], Galen, Benjamin T [0000-0001-8172-258X], Girard, Timothy D [0000-0002-9833-4871], Greenstein, Yonatan Y [0000-0002-5718-4408], Haniffa, Rashan [0000-0002-8288-449X], Hegde, Sheila M [0000-0001-8157-8899], Hendrickson, Carolyn M [0000-0003-4662-2385], Higgins, Alisa M [0000-0001-8295-7559], Hindenburg, Alexander A [0000-0002-1232-2168], Horvat, Christopher M [0000-0002-1593-2252], Huang, David T [0000-0001-7649-1633], Jacobson, Jeffrey R [0000-0001-8929-994X], Kim, Yuri [0000-0001-5978-5779], King, Andrew J [0000-0002-9809-0563], Kutcher, Matthew E [0000-0003-4566-5359], Leifer, Eric S [0000-0001-6888-8307], Litton, Edward [0000-0002-5125-6829], Mateos Garcia, Eduardo [0000-0002-0904-4056], Mouncey, Paul R [0000-0002-8510-8517], Nunez-Garcia, Brenda [0000-0002-0355-4557], Parnia, Sam [0000-0002-6158-4404], Quigley, John G [0000-0003-3116-4545], Saunders, Christina T [0000-0003-4325-9568], Yuriditsky, Eugene [0000-0003-2263-9297], Zhong, Yongqi [0000-0002-4042-7450], Neal, Matthew D [0000-0001-8931-6236], and Apollo - University of Cambridge Repository

Subjects
Male, Heparin, Critical Illness, Anticoagulants, COVID-19, Hemorrhage, Thrombosis, Middle Aged, Respiration, Artificial, COVID-19 Drug Treatment, Logistic Models, Odds Ratio, Humans, Female, Hospital Mortality, Treatment Failure, Aged
Abstract

BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

Published
2021

15. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Author

Lawler, Patrick R, Golighe, Ewan C, Berge, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kah, Susan RN, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Angus, Derek C, McArthur, Colin J, Webb, Steven A, Farkouh, Michael E, Hochman, Judith S, Zarychanski, Ryan, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Kreuziger, Lisa Baumann, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadzw, Tamta, Coiffard, Benjamin, Costantini, Todd W, de Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Dzavik, Vladimir, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Garcia-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, Kin, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Krishnan, Vidya, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Gregoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Lima, Felipe Gallego, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Moreno, Jose L Lopez-Sendon, Lother, Sylvain A, Malhotra, Saurabh, Marcos, Miguel, Marinez, Andrea Saud, Marshall, John C, Marten, Nicole, Matthay, Michael A, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Moore, Steven C, Guerreor, Raquel Morillo, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nunez-Garcia, Brenda, Pandey, Ambarish, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Gonzalez, Yessica S Perez, Pompilio, Mauricio, Prekker, Matthew E, Quigley, John G, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Santos, Mayler Olombrada, Satterwhite, Lewis, Saunders, Christina T, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Jr, Silva Delcio G, Shankar-Hari, Manu, Sheehan, John P, Singhal, Aneesh B, Solvaso, Dayna, Stanworth, Simon J, Tritschler, Tobias, Turner, Anne M, Van Bentum-Puijk, Wilma, van de Veerdonk, Frank L, van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Wells, Bryan J, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zampieri, Fernando G, Investigators, ATTACC, Investigators, ACTIV-4a, Investigators, REMAP-CAP, Investigators, ATTACC, Investigators, ACTIV-4a, Investigators, REMAP-CAP, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 215522, AR7-162822, CS-2016-16-011, RP-2015-06-18, National Institutes of Health, NIH: 1OT2HL156812-01, OTA-20-011, UL1TR001445, National Heart, Lung, and Blood Institute, NHLBI, Breast Cancer Research Foundation, BCRF, National Center for Advancing Translational Sciences, NCATS, New York University, NYU, Medical Center, University of Pittsburgh, CancerCare Manitoba Foundation, CCMF, University of Manitoba, UM, Health Research Board, HRB: CTN 2014-012, Canadian Institutes of Health Research, CIHR, National Institute for Health Research, NIHR, European Commission, EC: 602525, FP7-HEALTH-2013-INNOVATION, National Health and Medical Research Council, NHMRC: APP1101719, APP1116530, Health Research Council of New Zealand, HRC: 158584, 16/631, 447335, Canada Research Chairs, Eisai, Ministère des Affaires Sociales et de la Santé: PHRC-20-0147, Horizon 2020: 101003589, NIHR Imperial Biomedical Research Centre, BRC, Minderoo Foundation, The ATTACC platform was supported by grants from the Canadian Institutes of Health Research, LifeArc Foundation, Thistledown Foundation, Research Manitoba, Ontario Ministry of Health, Peter Munk Cardiac Centre, CancerCare Manitoba Foundation, and Victoria General Hospital Foundation. The ACTIV-4a platform was sponsored by the National Heart, Lung, and Blood Institute, National Institutes of Health (NIH) (grant numbers, OTA-20-011 and 1OT2HL156812-01). The pilot program (PROTECT) was funded in part by a grant (UL1TR001445) from the New York University Clinical and Translational Science Award program, supported by the National Center for Advancing Translational Sciences of the NIH. The REMAP-CAP platform was supported by the European Union through FP7-HEALTH-2013-INNOVATION: the Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium (602525) and the Horizon 2020 research and innovation program: the Rapid European Covid-19 Emergency Research response (RECOVER) consortium (101003589), by the Australian National Health and Medical Research Council (APP1101719 and APP1116530), the Health Research Council of New Zealand (16/631), the Canadian Institutes of Health Research (Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant [158584] and Covid-19 Rapid Research Operating Grant [447335]), the U.K. National Institute for Health Research (NIHR) and the NIHR Imperial Biomedical Research Centre, the Health Research Board of Ireland (CTN 2014-012), the Learning While Doing Program at the University of Pittsburgh Medical Center, the Breast Cancer Research Foundation, the French Ministry of Health (PHRC-20-0147), the Minderoo Foundation, Am-gen, Eisai, the Global Coalition for Adaptive Research, and the Wellcome Trust Innovations Project (215522). Dr. Goligher is the recipient of an Early Career Investigator award from the Canadian Institutes of Health Research (grant AR7-162822). Dr. Gordon is supported by an NIHR Research Professorship (RP-2015-06-18), Dr. Shankar-Hari by an NIHR Clinician Scientist Fellowship (CS-2016-16-011), and Dr. Turgeon by a Canada Research Chair (Tier 2). Dr. Zarychanski is the recipient of the Lyonel G. Israels Research Chair in Hematology (University of Manitoba)., Listed are data that were included in the analysis involving patients with moderate severity of coronavirus disease 2019 (Covid-19). The denominators of patients in the anticoagulation group and the thrombophylaxis group are un-equal owing to response-adaptive randomization. The baseline characteristics of the patients according to d-dimer level are provided in Table S2 in the Supplementary Appendix. To convert the values for creatinine to micromoles per liter, multiply by 88.4. ULN denotes upper limit of the normal range. † Race or ethnic group was reported by the patients. ‡ The body-mass index is the weight in kilograms divided by the square of the height in meters. § Severe cardiovascular disease was defined as a baseline history of heart failure, myocardial infarction, coronary artery disease, peripheral arterial disease, or cerebrovascular disease (stroke or transient ischemic attack) in the ATTACC (Antithrombotic Therapy to Ameliorate Complications of Covid-19) and ACTIV-4a (A Multicenter, Adaptive, Ran-domized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19) platforms and as a baseline history of New York Heart Association class IV symptoms in the REMAP-CAP platform (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia). ¶ Chronic respiratory disease was defined as a baseline history of asthma, chronic obstructive pulmonary disease, bron-chiectasis, interstitial lung disease, primary lung cancer, pulmonary hypertension, active tuberculosis, or the receipt of home oxygen therapy. ‖ Not listed are 74 patients who were coenrolled in the REMAP-CAP Antiplatelet Domain (39 in the anticoagulation group and 35 in the thromboprophylaxis group). ** In REMAP-CAP, levels of oxygen support (including no support) below the level of high-flow nasal cannula were not reported. †† The relative proportion of patients who were randomly assigned in each platform was imbalanced owing to imple-mentation of response-adaptive randomization in ATTACC on December 15, 2020. ‡‡ A total of 215 patients who were enrolled in the ATTACC platform were funded by the ACTIV4a platform by the National Heart, Lung, and Blood Institute. §§ Other participating countries were Mexico, Nepal, Australia, the Netherlands, and Spain., ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, Lawler, Patrick R [0000-0001-5155-5071], Neal, Matthew D [0000-0001-8931-6236], McVerry, Bryan J [0000-0002-1175-4874], Carrier, Marc [0000-0001-8296-2972], Escobedo, Jorge [0000-0003-1942-7402], Huang, David T [0000-0001-7649-1633], Bradbury, Charlotte A [0000-0001-5248-8165], Houston, Brett L [0000-0002-8776-4083], Kornblith, Lucy Z [0000-0002-1861-9691], Kim, Keri S [0000-0002-8480-4801], Gordon, Anthony C [0000-0002-0419-547X], Higgins, Alisa M [0000-0001-8295-7559], Aday, Aaron W [0000-0001-6243-3432], Aryal, Diptesh [0000-0002-1431-8293], Baumann Kreuziger, Lisa [0000-0002-1171-0548], Beane, Abi [0000-0001-7046-1580], Coiffard, Benjamin [0000-0002-8896-5346], Derde, Lennie PG [0000-0002-3577-5629], Detry, Michelle A [0000-0002-2794-1439], Estcourt, Lise J [0000-0003-4309-9162], Everett, Brendan M [0000-0002-6331-5224], Galen, Benjamin T [0000-0001-8172-258X], Girard, Timothy D [0000-0002-9833-4871], Godoy, Lucas C [0000-0001-6171-1269], Greenstein, Yonatan Y [0000-0002-5718-4408], Haniffa, Rashan [0000-0002-8288-449X], Hanna, George [0000-0001-8737-3843], Hegde, Sheila M [0000-0001-8157-8899], Hendrickson, Carolyn M [0000-0003-4662-2385], Hite, R Duncan [0000-0002-2625-8750], Hindenburg, Alexander A [0000-0002-1232-2168], Horvat, Christopher M [0000-0002-1593-2252], Jacobson, Jeffrey R [0000-0001-8929-994X], Kim, Yuri [0000-0001-5978-5779], King, Andrew J [0000-0002-9809-0563], Kutcher, Matthew E [0000-0003-4566-5359], Lima, Felipe Gallego [0000-0003-1204-5743], Lopez-Sendon Moreno, Jose L [0000-0001-9414-3990], Marcos, Miguel [0000-0003-1269-4487], McGlothlin, Anna [0000-0002-9079-6166], Mouncey, Paul R [0000-0002-8510-8517], Nunez-Garcia, Brenda [0000-0002-0355-4557], Parnia, Sam [0000-0002-6158-4404], Quigley, John G [0000-0003-3116-4545], Saunders, Christina T [0000-0003-4325-9568], Shankar-Hari, Manu [0000-0002-5338-2538], Sheehan, John P [0000-0002-4328-2613], Tritschler, Tobias [0000-0002-8775-0511], Yuriditsky, Eugene [0000-0003-2263-9297], Zampieri, Fernando G [0000-0001-9315-6386], Angus, Derek C [0000-0002-7026-5181], Apollo - University of Cambridge Repository, NIHR, and National Institute for Health Research

Subjects
Male, covid-19, anticoagulation, [SDV]Life Sciences [q-bio], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 030204 cardiovascular system & hematology, heparin, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Hemorrhage/chemically induced, 030212 general & internal medicine, Hospital Mortality, Heparin/administration & dosage, anticoagulation, 11 Medical and Health Sciences, Anticoagulants/administration & dosage, Thrombosis/prevention & control, low molecular weight heparin, General Medicine, Heparin, Middle Aged, Thrombosis, Patient Discharge, 3. Good health, Coagulation, Original Article, Female, ATTACC Investigators, medicine.symptom, Covid-19, Life Sciences & Biomedicine, medicine.drug, Adult, medicine.medical_specialty, medicine.drug_class, adaptive platform trial, Low molecular weight heparin, Inflammation, Hemorrhage, COVID-19/drug therapy, 03 medical and health sciences, Medicine, General & Internal, General & Internal Medicine, medicine, Humans, Intensive care medicine, Survival analysis, Aged, Science & Technology, business.industry, SARS-CoV-2, Anticoagulants, COVID-19, Odds ratio, Heparin, Low-Molecular-Weight, medicine.disease, Survival Analysis, COVID-19 Drug Treatment, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Heparin, Low-Molecular-Weight/therapeutic use, ACTIV-4a Investigators, Human medicine, REMAP-CAP Investigators, business
Abstract

BACKGROUNDThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.METHODSIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.RESULTSThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.CONCLUSIONSIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589. opens in new tab, NCT04505774. opens in new tab, NCT02735707. opens in new tab, and NCT04359277. opens in new tab.)

Published
2021

16. Intracranial Hemorrhage and Early Mortality in Patients Receiving Extracorporeal Membrane Oxygenation for Severe Respiratory Failure.

Author

Arachchillage, Deepa R. J., Passariello, Maurizio, Laffan, Michael, Aw, T. C., Owen, Leah, Banya, Winston, Trimlett, Richard, Morgan, Cliff, Patel, Brijesh V., Pepper, John, and Ledot, Stephane

Subjects
BRAIN abscess, HEMORRHAGE, BRAIN tomography, MORTALITY, PREVENTION
Abstract

Intracranial hemorrhage (ICH) is a serious complication in patients receiving veno-venous extracorporealmembrane oxygenation (VV-ECMO) and is associated with highmortality. It is unknown whether ICH may be a consequence of the ECMO or of an underlying disease. The authors first aimed to assess the incidence of ICH at initiation and during the course of VV-ECMOand its associatedmortality. The secondaimwas to identify clinical and laboratory measures that could predict the development of ICH in severe respiratory failure. Data were collected from a total number of 165 patients receiving VV-ECMO from January, 2012 to December, 2016 in a single tertiary center and treated according to a single protocol. Only patients who had a brain computed tomography within 24 hours of initiation of ECMO (n = 149) were included for analysis. The prevalence and incidence of ICH at initiation and during the course of VV-ECMO (at median 9 days) were 10.7% (16/149) and 5.2% (7/133), respectively. Thrombocytopenia and reduced creatinine clearance (CrCL) were independently associated with increased risk of ICH on admission; odds ratio (95% confidence interval): 22.6 (2.6-99.5), and 10.8 (5.6-16.2). Only 30-day (not 180-day) mortality was significantly higher in patients with ICH on admission versus thosewithout (37.5% [6/16] vs 16.4% [22/133]; p = 0.03 and 43.7% [7/16] vs 26.3% [35/133]; p = 0.15, respectively). Reduced CrCL and thrombocytopenia were associated with ICH at initiation of VV-ECMO. The higher incidence of ICH at initiation suggests it ismore closely related to the severity of the underlying lung injury than to the VV-ECMO itself. ICH at VV-ECMO initiation was associated with early mortality. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
View/download PDF

17. Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis.

Author

Mumford, Andrew D., O'donnell, James, Gillmore, Julian D., Manning, Richard A., Hawkins, Philip N., and Laffan, Michael

Subjects
BLOOD coagulation disorders, HEMORRHAGE, AMYLOIDOSIS, PHYSIOLOGY, PATIENTS
Abstract

Haemorrhage is a frequent manifestation of amyloidosis. We performed a retrospective clinical analysis of 337 patients with systemic immunoglobulin light-chain (AL)-amyloidosis, in whom whole-body serum amyloid P component (SAP) scintigraphy and a clotting screen had been performed. Abnormal bleeding was noted in 94 cases (28%), and the coagulation screen was abnormal in 172 cases (51%). The most common abnormalities were prolongation of the thrombin time (TT; 108 cases, 32%) and the prothrombin time (PT; 82 cases, 24%). In multivariate analysis, a prolonged PT was the only coagulation abnormality associated with abnormal bleeding (P = 0·0012), but this was independent of the whole-body amyloid load. Prolongation of the TT was associated with hepatic amyloid infiltration (P < 0·00001), with proteinuria (P < 0·001) and low serum albumin (P < 0·00001). In 154 patients who were studied further, subnormal factor X activity (FX:C) was found in 22 cases (14%). In cases with subnormal FX:C, the corresponding factor X antigen (FX:Ag) measurements were consistently higher (median FX:Ag/FX:C 2·5, range 0·81–9·25, n = 16) than cases with normal FX:C (median FX:Ag/FX:C 0·96, range 0·65–1·29, n = 28, P < 0·0001). No evidence was found of an FX inhibitor. Of the 48/154 (31%) cases with a prolonged TT, the reptilase time was also prolonged in 38/48 cases (79%). These data show that haemorrhage and abnormal coagulation are common in AL-amyloidosis and are multifactorial in origin. We provide evidence suggesting that hepatic amyloid infiltration and nephrotic syndrome are determinants of the TT. In most patients, prolongation of the PT was explained by reduction in FX:C, but this was not wholly explained by a reduction in FX:Ag. [ABSTRACT FROM AUTHOR]

Published
2000
Full Text
View/download PDF

18. Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding

Author

Westbury, Sarah K, Canault, Matthias, Greene, Daniel, Bermejo, Emilse, Hanlon, Katharine, Lambert, Michele P, Millar, Carolyn M, Nurden, Paquita, Obaji, Samya G, Revel-Vilk, Shoshana, Van Geet, Chris, Downes, Kate, Papadia, Sofia, Tuna, Salih, Watt, Christopher, NIHR BioResource–Rare Diseases Consortium, Freson, Kathleen, Laffan, Michael A, Ouwehand, Willem H, Alessi, Marie-Christine, Turro, Ernest, and Mumford, Andrew D

Subjects
Blood Platelets, Male, Base Sequence, Mutation, Guanine Nucleotide Exchange Factors, Humans, Female, Hemorrhage, Alleles, 3. Good health, Pedigree
Abstract

Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterized. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in 3 pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5422 controls. Eleven cases harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. The variants included 5 high-impact variants predicted to prevent CalDAG-GEFI expression and 6 missense variants affecting the CalDAG-GEFI CDC25 domain, which mediates Rap1 activation during platelet inside-out αIIbβ3 signaling. Cases with biallelic RASGRP2 variants had abnormal mucocutaneous, surgical, and dental bleeding from childhood, requiring ≥1 blood or platelet transfusion in 78% of cases. Platelets displayed reduced aggregation in response to adenosine 5'-diphosphate and epinephrine, but variable aggregation defects with other agonists. There were no other consistent clinical or laboratory features. These data enable definition of human CalDAG-GEFI deficiency as a nonsyndromic, recessive PFD associated with a moderate or severe bleeding phenotype and complex defects in platelet aggregation.

19. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Author

ATTACC Investigators, ACTIV-4a Investigators, REMAP-CAP Investigators, Lawler, Patrick R, Goligher, Ewan C, Berger, Jeffrey S, Neal, Matthew D, McVerry, Bryan J, Nicolau, Jose C, Gong, Michelle N, Carrier, Marc, Rosenson, Robert S, Reynolds, Harmony R, Turgeon, Alexis F, Escobedo, Jorge, Huang, David T, Bradbury, Charlotte A, Houston, Brett L, Kornblith, Lucy Z, Kumar, Anand, Kahn, Susan R, Cushman, Mary, McQuilten, Zoe, Slutsky, Arthur S, Kim, Keri S, Gordon, Anthony C, Kirwan, Bridget-Anne, Brooks, Maria M, Higgins, Alisa M, Lewis, Roger J, Lorenzi, Elizabeth, Berry, Scott M, Berry, Lindsay R, Aday, Aaron W, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Costantini, Todd W, De Brouwer, Sophie, Derde, Lennie PG, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, García-Madrona, Sebastian, Girard, Timothy D, Godoy, Lucas C, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Hamburg, Naomi M, Haniffa, Rashan, Hanna, George, Hanna, Nicholas, Hegde, Sheila M, Hendrickson, Carolyn M, Hite, R Duncan, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Iyer, Vivek N, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei L, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Krishnan, Vidya, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Grégoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Lima, Felipe Gallego, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Lopez-Sendon Moreno, Jose L, Lother, Sylvain A, Malhotra, Saurabh, Marcos, Miguel, Saud Marinez, Andréa, Marshall, John C, Marten, Nicole, Matthay, Michael A, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Moore, Steven C, Morillo Guerrero, Raquel, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nunez-Garcia, Brenda, Pandey, Ambarish, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Pérez González, Yessica S, Pompilio, Mauricio, Prekker, Matthew E, Quigley, John G, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Olombrada Santos, Mayler, Satterwhite, Lewis, Saunders, Christina T, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Silva, Delcio G, Shankar-Hari, Manu, Sheehan, John P, Singhal, Aneesh B, Solvason, Dayna, Stanworth, Simon J, Tritschler, Tobias, Turner, Anne M, Van Bentum-Puijk, Wilma, Van De Veerdonk, Frank L, Van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Wells, Bryan J, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zampieri, Fernando G, Angus, Derek C, McArthur, Colin J, Webb, Steven A, Farkouh, Michael E, Hochman, Judith S, and Zarychanski, Ryan

Subjects
Adult, Male, Heparin, Anticoagulants, COVID-19, Hemorrhage, Thrombosis, Heparin, Low-Molecular-Weight, Middle Aged, Survival Analysis, 3. Good health, COVID-19 Drug Treatment, Humans, Female, Hospital Mortality, Aged
Abstract

BACKGROUND: Thrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19. METHODS: In this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care-level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level. RESULTS: The trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support-free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis. CONCLUSIONS: In noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.).

20. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19

Author

REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators, Goligher, Ewan C, Bradbury, Charlotte A, McVerry, Bryan J, Lawler, Patrick R, Berger, Jeffrey S, Gong, Michelle N, Carrier, Marc, Reynolds, Harmony R, Kumar, Anand, Turgeon, Alexis F, Kornblith, Lucy Z, Kahn, Susan R, Marshall, John C, Kim, Keri S, Houston, Brett L, Derde, Lennie PG, Cushman, Mary, Tritschler, Tobias, Angus, Derek C, Godoy, Lucas C, McQuilten, Zoe, Kirwan, Bridget-Anne, Farkouh, Michael E, Brooks, Maria M, Lewis, Roger J, Berry, Lindsay R, Lorenzi, Elizabeth, Gordon, Anthony C, Ahuja, Tania, Al-Beidh, Farah, Annane, Djillali, Arabi, Yaseen M, Aryal, Diptesh, Baumann Kreuziger, Lisa, Beane, Abi, Bhimani, Zahra, Bihari, Shailesh, Billett, Henny H, Bond, Lindsay, Bonten, Marc, Brunkhorst, Frank, Buxton, Meredith, Buzgau, Adrian, Castellucci, Lana A, Chekuri, Sweta, Chen, Jen-Ting, Cheng, Allen C, Chkhikvadze, Tamta, Coiffard, Benjamin, Contreras, Aira, Costantini, Todd W, De Brouwer, Sophie, Detry, Michelle A, Duggal, Abhijit, Džavík, Vladimír, Effron, Mark B, Eng, Heather F, Escobedo, Jorge, Estcourt, Lise J, Everett, Brendan M, Fergusson, Dean A, Fitzgerald, Mark, Fowler, Robert A, Froess, Joshua D, Fu, Zhuxuan, Galanaud, Jean P, Galen, Benjamin T, Gandotra, Sheetal, Girard, Timothy D, Goodman, Andrew L, Goossens, Herman, Green, Cameron, Greenstein, Yonatan Y, Gross, Peter L, Haniffa, Rashan, Hegde, Sheila M, Hendrickson, Carolyn M, Higgins, Alisa M, Hindenburg, Alexander A, Hope, Aluko A, Horowitz, James M, Horvat, Christopher M, Huang, David T, Hudock, Kristin, Hunt, Beverley J, Husain, Mansoor, Hyzy, Robert C, Jacobson, Jeffrey R, Jayakumar, Devachandran, Keller, Norma M, Khan, Akram, Kim, Yuri, Kindzelski, Andrei, King, Andrew J, Knudson, M Margaret, Kornblith, Aaron E, Kutcher, Matthew E, Laffan, Michael A, Lamontagne, Francois, Le Gal, Grégoire, Leeper, Christine M, Leifer, Eric S, Lim, George, Gallego Lima, Felipe, Linstrum, Kelsey, Litton, Edward, Lopez-Sendon, Jose, Lother, Sylvain A, Marten, Nicole, Saud Marinez, Andréa, Martinez, Mary, Mateos Garcia, Eduardo, Mavromichalis, Stavroula, McAuley, Daniel F, McDonald, Emily G, McGlothlin, Anna, McGuinness, Shay P, Middeldorp, Saskia, Montgomery, Stephanie K, Mouncey, Paul R, Murthy, Srinivas, Nair, Girish B, Nair, Rahul, Nichol, Alistair D, Nicolau, Jose C, Nunez-Garcia, Brenda, Park, John J, Park, Pauline K, Parke, Rachael L, Parker, Jane C, Parnia, Sam, Paul, Jonathan D, Pompilio, Mauricio, Quigley, John G, Rosenson, Robert S, Rost, Natalia S, Rowan, Kathryn, Santos, Fernanda O, Santos, Marlene, Santos, Mayler O, Satterwhite, Lewis, Saunders, Christina T, Schreiber, Jake, Schutgens, Roger EG, Seymour, Christopher W, Siegal, Deborah M, Silva, Delcio G, Singhal, Aneesh B, Slutsky, Arthur S, Solvason, Dayna, Stanworth, Simon J, Turner, Anne M, Van Bentum-Puijk, Wilma, Van De Veerdonk, Frank L, Van Diepen, Sean, Vazquez-Grande, Gloria, Wahid, Lana, Wareham, Vanessa, Widmer, R Jay, Wilson, Jennifer G, Yuriditsky, Eugene, Zhong, Yongqi, Berry, Scott M, McArthur, Colin J, Neal, Matthew D, Hochman, Judith S, Webb, Steven A, and Zarychanski, Ryan

Subjects
Male, Heparin, Critical Illness, Anticoagulants, COVID-19, Hemorrhage, Thrombosis, Middle Aged, Respiration, Artificial, 3. Good health, COVID-19 Drug Treatment, Logistic Models, Odds Ratio, Humans, Female, Hospital Mortality, Treatment Failure, Aged
Abstract

BACKGROUND: Thrombosis and inflammation may contribute to morbidity and mortality among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19. METHODS: In an open-label, adaptive, multiplatform, randomized clinical trial, critically ill patients with severe Covid-19 were randomly assigned to a pragmatically defined regimen of either therapeutic-dose anticoagulation with heparin or pharmacologic thromboprophylaxis in accordance with local usual care. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. RESULTS: The trial was stopped when the prespecified criterion for futility was met for therapeutic-dose anticoagulation. Data on the primary outcome were available for 1098 patients (534 assigned to therapeutic-dose anticoagulation and 564 assigned to usual-care thromboprophylaxis). The median value for organ support-free days was 1 (interquartile range, -1 to 16) among the patients assigned to therapeutic-dose anticoagulation and was 4 (interquartile range, -1 to 16) among the patients assigned to usual-care thromboprophylaxis (adjusted proportional odds ratio, 0.83; 95% credible interval, 0.67 to 1.03; posterior probability of futility [defined as an odds ratio

21. Acquired factor VIII inhibitor associated with lung abscess.

Author

Ganly, Peter S., Isaacs, John D., Laffan, Michael A., Haslett, Christopher, and Hows, Jill M.

Subjects
HEMORRHAGE, BRONCHITIS, PROGNOSIS
Abstract

Describes a case on hemoptysis in chronic bronchitis involving a seventy-year old male. Impact of bleeding disorder on the disease; Factor effecting development of coagulopathy; Implications of presence of other medical problems for the management of patient.

Published
1987
Full Text
View/download PDF

22. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A.

Author

Pasi, K. John, Rangarajan, Savita, Mitchell, Nina, Lester, Will, Symington, Emily, Madan, Bella, Laffan, Michael, Russell, Chris B., Mingjin Li, Pierce, Glenn F., Wong, Wing Y., and Li, Mingjin

Subjects
*GENE therapy, *BLOOD coagulation factor VIII, *BLOOD coagulation factor VIII antibodies, *HEMOPHILIA, *BIOMARKERS, *ADENO-associated virus, *BODY weight, *HEMORRHAGE prevention, *HEMOPHILIA treatment, *HEMOPHILIA complications, *RESEARCH, *VIRUSES, *INTRAVENOUS therapy, *CLINICAL trials, *RESEARCH methodology, *EVALUATION research, *MEDICAL cooperation, *COMPARATIVE studies, *GENES, *BLOOD coagulation factors, *LONGITUDINAL method, *HEMORRHAGE, BLOOD coagulants
Abstract

Background: Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ.Methods: We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years.Results: Three years after infusion, two participants (one who had received 6×1012 vector genomes [vg] per kilogram of body weight and one who had received 2×1013 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×1013 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×1013 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed.Conclusions: Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×1013 vg per kilogram or 6×1013 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.). [ABSTRACT FROM AUTHOR]

Published
2020
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results